The present invention relates to a neurotrophic factor secretagogue being useful in the treatment of neurodegenerative diseases, etc.
Nitric oxide (NO) is a free radical gas, which was found as an endogenous factor being produced by vascular endothelial cells, and it has been known to be involved with the regulation of vascular tone, platelet aggregation, neurotransmission mechanism and immune activation (Reference 1). It is reported that NO exhibits a neurotransmitter-like activity in the central nervous system, and is involved with the long term potentiation (LTP) and the learning memory (References 2, 3, 4 and 5).
However, the connection between NO and neuro-degenerative diseases (Alzheimer""s disease, Amyotrophic lateral sclerosis, etc.) has not been clarified yet. Although several studies have been done using some techniques such as component analysis of cerebrospinal fluid from patients (Reference 6) and histological analysis of brains (Reference 7), there is no decided indication as to the connection between the NO producing system in tissue and the pathogenesis of these diseases. Further, it is rather a common concept that the increase in NO amount in tissues is not useful in the treatment of neurodegenerative diseases. Recently, many patent applications have been filed as to technical ideas of treatment of neuro-degenerative diseases by administering an NO synthase inhibitor in order to reduce the NO production in neural cells (References 8 and 9), these patent applications are based on a hypothesis that NO may be toxic to neural cells, and the technical idea of the present invention is completely different from those of these patent applications.
Exceptionally, there is a patent application suggesting the treatment of central nervous diseases by NO synthesis acceleration (Reference 10), but the method thereof is that the NO concentration in blood is increased by ozone gas and ultraviolet irradiation by which platelet aggregation-related diseases, hypertension, depression, infections, and impotence are cured. Depression is not a neurodegenerative disease, nor is cured by a neurotrophic factor. Besides, said application never discloses or suggests the technical idea of the present invention that an NO donor being exogenously administered enhances the secretion of neurotrophic factors.
In addition, it is reported that Interleukin-1 (IL-1), Prostaglandin, Tumor Necrosis Factor (TNF), Fibroblast growth factor (FGF), etc. show activities of enhancing neurotrophic factor secretion, especially NGF, but it is not reported yet that an NO donor promotes the secretion of a neurotrophic factor, especially BDNF, in neural cells.
Reference 1: Snyder et al.: Scientific American, p. 28-35 (1992.5)
Reference 2: Haley, J. et al.: Neuron 8, 211-216 (1992)
Reference 3: Schuman, E. M. and Madison, D. V.: Ann. Rev. Neurosci. 17, 153-183 (1994)
Reference 4: Toyoda, M S et al.: Jpn. J. Pharmacol. 71, 205-211 (1996)
Reference 5: Yamada, K et al.: Neuroscience 74 (2), 365-374 (1996)
Reference 6: Milstein, S et al.: J. Neurochemistry 63 (3), 1178-1180 (1994)
Reference 7: Rebeck, G. W. et al.: Neuroscience letters 152, 165-168 (1993)
Reference 8: JP-A-4-270255 (EP 446699): Merrell Dow Pharmaceuticals Inc.
Reference 9: WO 96/14842: Merck and Co., Inc.
Reference 10: JP-A-7-503722 (WO 93/15779): Vasogen, Inc.
Neurotrophic factors such as BDNF are expected to exhibit pharmacological activities on neurodegenerative diseases, nerve damages by ischemia or injury, or moreover on optic nerve damages. These factors are inherently proteins expressed and secreted in the living body, and a lower molecular weight compound which can promote the secretion of these proteins is considered to be useful in the clinical field. An object of the present invention is to provide a medicament comprising as an active ingredient a lower molecular weight compound, and being capable of promoting the neurotrophic factor activities in the living body, that is, an agent for treatment of diseases being responsive to neurotrophic factors.
That is, the gist of the present invention is below.
[1] A neurotrophic factor secretagogue, which comprises as an active ingredient an NO donor.
[2] The neurotrophic factor secretagogue according to the above [1], wherein the NO donor is a spontaneous NO donor.
[3] The neurotrophic factor secretagogue according to the above [1], which is administered to a human for the treatment of a neurodegenerative disease.
[4] A neurotrophin secretagogue, which comprises as an active ingredient an NO donor.
[5] A BNDF secretagogue, which comprises as an active ingredient an NO donor.